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Downregulation of CEMIP enhances radiosensitivity by promoting DNA damage and apoptosis in colorectal cancer

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Abstract

Colorectal cancer (CRC) is the third leading malignancy worldwide in both new cases and deaths. Neoadjuvant radiotherapy is the standard preoperative regimens for locally advanced patients. However, approximately 50% of patients develop recurrence and metastasis after radiotherapy, which is largely due to the radiation resistance properties of the tumor, and the internal mechanism has not been elucidated. Here we found that CEMIP expression is up-regulated in a variety of tumor types, particularly in CRC. Public databases and clinical samples revealed that CEMIP expression is significantly higher in tumor tissues than in adjacent normal tissues in patients with locally advanced CRC who received neoadjuvant chemoradiotherapy, and it is closely related to the poor prognosis. Functional characterization uncovered that downregulation of CEMIP expression can enhance the radiosensitivity of CRC cells, which is confirmed to be achieved by promoting DNA damage and apoptosis. In vivo studies further verified that CEMIP knockdown can significantly improve the radiosensitivity of subcutaneously implanted colorectal tumors in mice, suggesting that CEMIP may be a radiation-resistant gene in CRC. Mechanistically, EGFR/PI3K/Akt signaling pathway is hypothesized to play a key role in CEMIP mediating radiation resistance. These results provide a potential new strategy targeting CEMIP gene for the comprehensive treatment of locally advanced CRC patients.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China 81803063 to Yiyi Li, 82273564, 82073342, 81872470 to Yi Ding, 81903125 to Yuqin Zhang, and 82170647 to Kai Wang, the Natural Science Foundation of Guangdong, China 2018030310297 to Yiyi Li, and 2020A1515011205 to Kai Wang, the Science and Technology Program of Guangzhou, China 202102020976 to Yiyi Li, and 202206010045 to Yi Ding.

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Author notes

  1. Jiawen Weng and Yuqin Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Jiawen Weng, Yuqin Zhang, Weijie Liang, Yuwen Xie, Yi Ding & Yiyi Li

  2. Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Kai Wang

  3. The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Jiawen Weng & Qian Xu

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  1. Jiawen Weng
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JW, YZ, WL, YX, KW and QX. The first draft of the manuscript was written by YL and YD. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yi Ding or Yiyi Li.

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The authors have no relevant financial or non-financial interests to disclose.

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The protocol was approved by the institutional ethics committee (Identifier: NFEC-2022-367), and all patients provided written informed consent.

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Weng, J., Zhang, Y., Liang, W. et al. Downregulation of CEMIP enhances radiosensitivity by promoting DNA damage and apoptosis in colorectal cancer. Med Oncol 40, 73 (2023). https://doi.org/10.1007/s12032-022-01940-4

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  • DOI: https://doi.org/10.1007/s12032-022-01940-4

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